Glioblastoma (GBM) is the most fatal brain tumor, showing a very limited survival rate in spite of best treatment. Standard first line therapy is a surgery followed by concurrent temozolomide (TMZ) treatment and radiation. According to NCCN guidelines of central nervous system cancer, only a third of patients survive for one year and less than 5% live beyond 5 years. Temozolomide, an alkylating (methylating) agent, is now the standard of care in conjunction with postoperative RT for younger, good performance patients with GBM. However, the patients ultimately succumb to death by the relapse of the disease.
A growing body of evidence that supports the idea that cancers are initiated and maintained by a subpopulation of cells is being reported. The presence of CSCs raises the clinical implication that a curative therapy will require complete elimination of this unique population even in patients with an initial response to treatment, since the disease may ultimately recur if even a small number of CSCs survive the therapy. Accumulated evidence has established that CSC populations are more resistant to conventional cancer therapy than non-CSC populations. For example, CD133 positive GBM CSCs displayed strong capability on tumors' resistance to chemotherapy and radiotherapy. Consequently, novel therapeutic systems have been developed with the purpose of targeting CSCs and altering the microenvironment in which these cells potentially reside. Targeting the surface of markers, signaling cascades, and microenvironments have been tried and examined.
Since studies have unveiled that the biguanide derivate metformin (N′,N′-dimethylbiguanide), the most widely used oral therapeutic agent for lowering blood glucose concentrations in patients with type 2 diabetes, significantly reduces cancer incidence and improves cancer patients' survival in type 2 diabetics, laboratory evidence of an antineoplastic effect of biguanide has been accumulated and the first generation of clinical trials on metformin in progress is anticipated. Direct action of biguanides on transformed cells or cells at risk for transformation was attributed to a consequence of homeostatic response to the agent-induced energetic stress or may be attributed to energy depletion by the inhibition of oxidative phosphorylation (OXPHOS), which leads to the energy conservation state or AMPK activation within the cells, but this is still under investigation. Remarkably, Hirsch et al. have demonstrated that mass-forming, self-renewing tumor-initiating breast cancer cells seems to exhibit an exacerbated sensitivity to metformin (Hirsch H A, Iliopoulos D, Tsichlis P N, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer research. 2009; 69(19):7507-7511). This group suggests that TGF-β-induced EMT might represent a common molecular mechanism underlying the anti-cancer stem cells action of metformin (Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez J A. Metformin against TGFbeta-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell cycle, 2010; 9(22):4461-4468,). However, supporting studies for this notion are still limited.
In the present study, we assessed the effect of 1IL56A alone or combined with a previously known agent, temozolomide, on the stem cell properties and survival of orthotopic xenografted animals, to evaluate the feasibility of a new drug, alone or combined with the conventional therapeutic agent TMZ, in the treatment of GBM.